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10 sources retrieved Β· Most recent: April 2026 Β· Index updated 15 days ago
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INPP4A
inositol polyphosphate-4-phosphatase type I A
Chromosome 2 Β· 2q11.2
NCBI Gene: 3631Ensembl: ENSG00000040933.17HGNC: HGNC:6074UniProt: A0ABB0MUY6
42PubMed Papers
20Diseases
0Drugs
8Pathogenic Variants
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
protein bindingcytoplasmnucleusnucleoplasmIntellectual disabilitymicrocephalyHypotoniaPectus excavatum
✦AI Summary

INPP4A (inositol polyphosphate-4-phosphatase type I A) is a lipid phosphatase that hydrolyzes phosphatidylinositol 3,4-bisphosphate to generate phosphatidylinositol-3-phosphate 1. The enzyme localizes to multiple cellular compartments including the cytoplasm, nucleus, and perinuclear clusters associated with the endosomal marker Rab5, with subcellular distribution varying by INPP4A isoform 2. Mechanistically, INPP4A negatively regulates the PI3K/Akt signaling pathway 3 and can form a functional complex with cytochrome c to suppress ferroptosis by preventing lipid peroxidation 1. Biallelic INPP4A variants cause a spectrum of neurodevelopmental disorders ranging from moderate intellectual disability to severe presentations featuring postnatal microcephaly, developmental delay, myoclonic seizures, and (ponto)cerebellar hypoplasia 42. Disease severity correlates with variant location; mutations downstream of exon 4 produce more severe phenotypes, while upstream variants may permit translational reinitiation generating N-terminally truncated proteins with partial function 4. Beyond neurodevelopment, INPP4A dysregulation contributes to allergic and inflammatory diseases: deficiency promotes M2 macrophage polarization in eosinophilic chr2 rhinosinusitis 5, while reduced extracellular INPP4A associates with asthma pathogenesis 3. INPP4A represents an important regulator of cell proliferation, apoptosis, and endosomal trafficking with therapeutic potential across multiple disease contexts.

Sources cited
1
INPP4A (inositol polyphosphate-4-phosphatase type I A) is a lipid phosphatase that hydrolyzes phosphatidylinositol 3,4-bisphosphate to generate phosphatidylinositol-3-phosphate .
PMID: 40233758
2
The enzyme localizes to multiple cellular compartments including the cytoplasm, nucleus, and perinuclear clusters associated with the endosomal marker Rab5, with subcellular distribution varying by INPP4A isoform .
PMID: 36653678
3
Mechanistically, INPP4A negatively regulates the PI3K/Akt signaling pathway and can form a functional complex with cytochrome c to suppress ferroptosis by preventing lipid peroxidation .
PMID: 30335467
4
Biallelic INPP4A variants cause a spectrum of neurodevelopmental disorders ranging from moderate intellectual disability to severe presentations featuring postnatal microcephaly, developmental delay, myoclonic seizures, and (ponto)cerebellar hypoplasia , .
PMID: 39315527
5
Beyond neurodevelopment, INPP4A dysregulation contributes to allergic and inflammatory diseases: deficiency promotes M2 macrophage polarization in eosinophilic chr2 rhinosinusitis , while reduced extracellular INPP4A associates with asthma pathogenesis .
PMID: 38363325
Disease Associationsβ“˜20
Intellectual disabilityOpen Targets
0.39Weak
microcephalyOpen Targets
0.27Weak
dyskeratosis congenitaOpen Targets
0.27Weak
HypotoniaOpen Targets
0.27Weak
NystagmusOpen Targets
0.27Weak
Pectus excavatumOpen Targets
0.27Weak
placenta praeviaOpen Targets
0.26Weak
SeizureOpen Targets
0.23Weak
celiac diseaseOpen Targets
0.21Weak
lower urinary tract calculusOpen Targets
0.20Weak
complex neurodevelopmental disorderOpen Targets
0.18Weak
idiopathic pulmonary fibrosisOpen Targets
0.07Suggestive
pulmonary fibrosisOpen Targets
0.07Suggestive
Dysequilibrium syndromeOpen Targets
0.07Suggestive
Adult-onset autosomal recessive cerebellar ataxiaOpen Targets
0.07Suggestive
Spinocerebellar ataxia type 41Open Targets
0.06Suggestive
Rare hereditary ataxiaOpen Targets
0.06Suggestive
Spinocerebellar ataxia type 40Open Targets
0.06Suggestive
spinocerebellar ataxia type 12Open Targets
0.06Suggestive
Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxiaOpen Targets
0.06Suggestive
Pathogenic Variants8
NM_001134225.2(INPP4A):c.352_353del (p.Ser118fs)Likely pathogenic
Microcephaly;Pectus excavatum;visual disturbance;Hypotonia;Nystagmus|Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech
β˜…β˜†β˜†β˜†2019β†’ Residue 118
NM_001134225.2(INPP4A):c.36C>T (p.Ala12=)Likely pathogenic
Dyskeratosis congenita, autosomal dominant 1
β˜…β˜†β˜†β˜†2017β†’ Residue 12
NM_001134225.2(INPP4A):c.981del (p.Asp328fs)Pathogenic
Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech
β˜†β˜†β˜†β˜†2025β†’ Residue 328
NM_001134225.2(INPP4A):c.646C>T (p.Arg216Ter)Pathogenic
Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech
β˜†β˜†β˜†β˜†2025β†’ Residue 216
NM_001134225.2(INPP4A):c.1567-81_1822+1434delPathogenic
Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech
β˜†β˜†β˜†β˜†2025
NM_001134225.2(INPP4A):c.106+1G>APathogenic
Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech
β˜†β˜†β˜†β˜†2025
NM_001134225.2(INPP4A):c.2278C>T (p.Arg760Cys)Pathogenic
Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech
β˜†β˜†β˜†β˜†2025β†’ Residue 760
NM_001134225.2(INPP4A):c.115C>T (p.Gln39Ter)Pathogenic
Intellectual disability
β˜†β˜†β˜†β˜†2019β†’ Residue 39
View on ClinVar β†—
Related Genes
INPPL1Protein interaction96%INPP5BProtein interaction95%PTENProtein interaction95%PIK3R2Protein interaction95%INPP4BProtein interaction94%INPP5DProtein interaction94%
Tissue Expression6 tissues
Brain
100%
Bone Marrow
77%
Heart
73%
Lung
58%
Ovary
44%
Liver
28%
Gene Interaction Network
Click a node to explore
INPP4AINPPL1INPP5BPTENPIK3R2INPP4BINPP5D
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted Β· UniProt Q96PE3
View on AlphaFold β†—
Constraintβ“˜
LOEUFβ“˜
0.41Moderately Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.29 [0.20–0.41]
RankingsWhere INPP4A stands among ~20K protein-coding genes
  • #9,888of 20,598
    Most Researched42
  • #3,104of 5,498
    Most Pathogenic Variants8
  • #2,121of 17,882
    Most Constrained (LOEUF)0.41 Β· top quartile
Genes detectedINPP4A
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Cytosolic cytochrome c represses ferroptosis.
PMID: 40233758
Cell Metab Β· 2025
1.00
2
The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families.
PMID: 36344539
Sci Rep Β· 2022
0.90
3
INPP4A-related genetic and phenotypic spectrum and functional relevance of subcellular targeting of INPP4A isoforms.
PMID: 36653678
Neurogenetics Β· 2023
0.80
4
Deficiency of INPP4A promotes M2 macrophage polarization in eosinophilic chronic rhinosinusitis with nasal polyps.
PMID: 38363325
Inflamm Res Β· 2024
0.70
5
Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.
PMID: 39315527
Genet Med Β· 2025
0.60